Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Ester doai
Reexamination Certificate
2003-02-05
2004-09-14
Richter, Johann (Department: 1621)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Ester doai
C514S567000, C560S039000, C562S444000
Reexamination Certificate
active
06790865
ABSTRACT:
TECHNICAL FIELD
The present invention relates to novel 2-methylpropionic acid derivatives and pharmaceutically acceptable salts thereof which are useful as medicaments.
BACKGROUND ART
It is known that three subtypes of sympathetic &bgr;-adrenoceptors, which have been classified as &bgr;
1
, &bgr;
2
and &bgr;
3
, are present and that each receptor subtype is distributed in specified organs in living body and has a specific function.
For example, &bgr;
1
-adrenoceptor is mainly present in the heart and the stimulation of this receptor leads to an increase of heart rate and cardiac contractility. &bgr;
2
-Adrenoceptor is mainly present in the smooth muscle of blood vessels, the trachea and uterus. The stimulation of this receptor leads to vasodilatation, bronchodilation and inhibition of uterine contraction. &bgr;
3
-Adrenoceptor is mainly present in adipocytes, the gallbladder and intestinal tract. It is known that &bgr;
3
-adrenoceptor is also present in the brain, liver, stomach and prostate. It is reported that the stimulation of this receptor leads to an increase of lipolysis, inhibition of intestinal tract motility, an increase of glucose uptake, anti-depression and so on (Drugs of the Future, Vol.18, No.6, pp.529-549 (1993); Molecular Brain Research, Vol.29, pp.288-297 (1995);
In addition, it is recently reported that in the human bladder &bgr;
3
-adrenoceptor is predominantly present and that the human bladder is relaxed by &bgr;
3
-adrenoceptor stimulants (The Japanese Journal of Urology, Vol.88, No.2, p.183 (1997); NEUROUROLOGY AND URODYNAMICS, Vol.16, No.5, pp.363-365 (1997)).
Many &bgr;
1
-adrenoceptor stimulants and &bgr;
2
-adrenoceptor stimulants have been developed and are used for medicinal purposes as cardiotonics, bronchodilators, preventive agents for threatened abortion or premature labor, and so on.
On the other hand, it has been found that &bgr;
3
-adrenoceptor stimulants are useful as agents for the prevention or treatment of obesity, hyperglycemia, the diseases caused by intestinal hypermotility, pollakiuria, urinary incontinence, depression, the diseases caused by biliary calculi or hypermotility of biliary tract and so on. Consequently, studies have been made to develop excellent &bgr;
3
-adrenoceptor stimulants, but no &bgr;
3
-adrenoceptor stimulant has been sold yet (Drugs of the Future, Vol.18, No.6, pp.529-549(1993); European Journal of Pharmacology, Vol.219, pp.193-201(1992) etc.).
Therefore, it has been greatly desired to develop novel &bgr;
3
-adrenoceptor stimulants having excellent &bgr;
3
-adrenoceptor stimulating effects.
More preferably, it has been desired to develop highly selective and novel &bgr;
3
-adrenoceptor stimulants having potent &bgr;
3
-adrenoceptor stimulating effects in comparison with &bgr;
1
and/or &bgr;
2
-adrenoceptor stimulating effects and resulting in reduced side effects such as palpitation and tremor caused by &bgr;
1
and &bgr;2-adrenoceptor stimulating effects.
DISCLOSURE OF THE INVENTION
The present invention relates to a 2-methylpropionic acid derivative represented by the general formula:
(wherein R
1
represents a hydrogen atom, a lower alkyl group or an aralkyl group; R
2
represents a hydrogen atom, a lower alkyl group or a halogen atom; A represents an oxygen atom or an imino group; the carbon atom marked with (R) represents a carbon atom in R configuration; and the carbon atom marked with (S) represents a carbon atom in S configuration) or a pharmaceutically acceptable salt thereof.
The present invention relates to a pharmaceutical composition comprising as the active ingredient a 2-methyl-propionic acid derivative represented by the above general formula (I) or a pharmaceutically acceptable salt thereof.
The present invention relates to an agent for the prevention or treatment of obesity, hyperglycemia, the diseases caused by intestinal hypermotility, pollakiuria, urinary incontinence, depression, or the diseases caused by biliary calculi or hypermotility of biliary tract which comprises as the active ingredient a 2-methylpropionic acid derivative represented by the above general formula (I) or a pharmaceutically acceptable salt thereof.
The present invention relates to a method for the prevention or treatment of obesity, hyperglycemia, the diseases caused by intestinal hypermotility, pollakiuria, urinary incontinence, depression, or the diseases caused by biliary calculi or hypermotility of biliary tract which comprises administering a therapeutically effective amount of a 2-methylpropionic acid derivative represented by the above general formula (I) or a pharmaceutically acceptable salt thereof.
The present invention relates to a use of a 2-methyl-propionic acid derivative represented by the above general formula (I) or a pharmaceutically acceptable salt thereof for the manufacture of a pharmaceutical composition for the prevention or treatment of obesity, hyperglycemia, the diseases caused by intestinal hypermotility, pollakiuria, urinary incontinence, depression, or the diseases caused by biliary calculi or hypermotility of biliary tract.
The present invention relates to a use of a 2-methyl-propionic acid derivative represented by the above general formula (I) or a pharmaceutically acceptable salt thereof as an agent for the prevention or treatment of obesity, hyperglycemia, the diseases caused by intestinal hypermotility, pollakiuria, urinary incontinence, depression, or the diseases caused by biliary calculi or hypermotility of biliary tract.
The present invention relates to a process for the manufacture of a pharmaceutical composition for the prevention or treatment of obesity, hyperglycemia, the diseases caused by intestinal hypermotility, pollakiuria, urinary incontinence, depression, or the diseases caused by biliary calculi or hypermotility of biliary tract, characterized in the use, as an essential constituent, of a 2-methylpropionic acid derivative represented by the above general formula (I) or a pharmaceutically acceptable salt thereof.
BEST MODE FOR CARRYING OUT THE INVENTION
The present inventors have studied extensively to meet the above objects. As a result, it was found that 2-methyl-propionic acid derivatives represented by the above general formula (I) and pharmaceutically acceptable salts thereof have excellent
62
3
-adrenoceptor stimulating effects, thereby forming the basis of the present invention.
In the present invention, the term “lower alkyl group” means a straight or branched alkyl group having 1 to 6 carbon atoms such as a methyl group, an ethyl group, a propyl group, an isopropyl group, a butyl group, a sec-butyl group, a tert-butyl group, an isobutyl group, a pentyl group, an isopentyl group, a hexyl group and the like; the term “aralkyl group” means the above lower alkyl group substituted by an aryl group such as a phenyl group, a naphthyl group and the like; and the term “halogen atom” means a fluorine atom, a chlorine atom, a bromine atom and the like.
The compounds represented by the above general formula (I) of the present invention can be prepared according to the following procedure. For example, the compounds of the present invention can be prepared by allowing an amine compound represented by the formula:
(wherein the carbon atom marked with (R) and the carbon atom marked with (S) have the same meanings as defined above) to react with an alkylating agent represented by the general formula:
(wherein R
1a
represents a lower alkyl group or an aralkyl group; X represents a leaving group; and R
2
and A have the same meanings as defined above) in the presence or absence of a base such as N,N-diisopropylethylamine in an inert solvent such as N,N-dimethylformamide, and converting the ester group into a carboxyl group in the usual way as occasion demands.
The amine compound represented by the above formula (II) which is used as a starting material in the above production process can be prepared by optical resolution of a commercially available enantiomeric mixture in the usual way or a method described in a literature (e.g., J. Med. Chem., Vol. 20, No. 7, pp.978-9
Akahane Masuo
Hirabayashi Akihito
Mukaiyama Harunobu
Muranaka Hideyuki
Sato Masa-aki
Kissei Pharmaceutical Co. Ltd.
Richter Johann
Zucker Paul A.
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